tbuckley/cabot-search huggingface dataset:
Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity
Authors: Morgane Boulch, Marine Cazaux, Alexis Cuffel, Marion V. Guerin, Zacarias Garcia, Ruby Alonso, Fabrice Lemaître, Alexander Beer, Béatrice Corre, Laurie Menger, Capucine L. Grandjean, Florence Morin, Catherine Thieblemont, Sophie Caillat-Zucman, Philippe Bousso
Journal: Nature Cancer (2023)

Abstract CD4 + T cells and CD4 + chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4 + T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4 + CAR T cells. Mechanistically, mouse or human CD4 + CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4 + CAR T-cell efficacy and may be considered to guide the use of CD4 + T cells during immunotherapy.
The Role of Introgression During the Radiation of Endemic Fishes Adapted to Living at Extreme Altitudes in the Tibetan Plateau
Authors: Yuting Qian, Minghui Meng, Chaowei Zhou, Haiping Liu, Haifeng Jiang, Youwei Xu, Wenjun Chen, Zufa Ding, Yang Liu, Xiong Gong, Cheng Wang, Yi Lei, Tai Wang, Ying Wang, Xiaoni Gan, Axel Meyer, Shunping He, Liandong Yang
Journal: Molecular Biology and Evolution (2023)

Abstract Recent genomic analyses of evolutionary radiations suggest that ancient introgression may facilitate rapid diversification and adaptive radiation. The loach genus Triplophysa, a genus with most species endemic to Tibetan Plateau, shows ecological diversity and rapid evolution and represents a potential example of adaptive radiation linked to the uplift of the Tibetan Plateau. Here, we interrogate the complex evolutionary history of Triplophysa fishes through the analysis of whole-genome sequences. By reconstructing the phylogeny of Triplophysa, quantifying introgression across this clade, and simulating speciation and migration processes, we confirm that extensive gene flow events occurred across disparate Triplophysa species. Our results suggest that introgression plays a more substantial role than incomplete lineage sorting in underpinning phylogenetic discordance in Triplophysa. The results also indicate that genomic regions affected by ancient gene flow exhibit characteristics of lower recombination rates and nucleotide diversity and may associate with selection. Simulation analysis of Triplophysa tibetana suggests that the species may have been affected by the Gonghe Movement in the third uplift of the Tibetan Plateau, resulting in founder effects and a subsequent reduction in Ne.
Accelerated Evolution Analysis Uncovers <i>PKNOX2</i> as a Key Transcription Factor in the Mammalian Cochlea
Authors: Anabella P Trigila, Valeria C Castagna, Lara Berasain, Dante Montini, Marcelo Rubinstein, Maria Eugenia Gomez-Casati, Lucía F Franchini
Journal: Molecular Biology and Evolution (2023)

The genetic bases underlying the evolution of morphological and functional innovations of the mammalian inner ear are poorly understood. Gene regulatory regions are thought to play an important role in the evolution of form and function. To uncover crucial hearing genes whose regulatory machinery evolved specifically in mammalian lineages, we mapped accelerated noncoding elements (ANCEs) in inner ear transcription factor (TF) genes and found that PKNOX2 harbors the largest number of ANCEs within its transcriptional unit. Using reporter gene expression assays in transgenic zebrafish, we determined that four PKNOX2-ANCEs drive differential expression patterns when compared with ortholog sequences from close outgroup species. Because the functional role of PKNOX2 in cochlear hair cells has not been previously investigated, we decided to study Pknox2 null mice generated by CRISPR/Cas9 technology. We found that Pknox2-/- mice exhibit reduced distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) thresholds at high frequencies together with an increase in peak 1 amplitude, consistent with a higher number of inner hair cells (IHCs)-auditory nerve synapsis observed at the cochlear basal region. A comparative cochlear transcriptomic analysis of Pknox2-/- and Pknox2+/+ mice revealed that key auditory genes are under Pknox2 control. Hence, we report that PKNOX2 plays a critical role in cochlear sensitivity at higher frequencies and that its transcriptional regulation underwent lineage-specific evolution in mammals. Our results provide novel insights about the contribution of PKNOX2 to normal auditory function and to the evolution of high-frequency hearing in mammals.
Menstrual cycle length variation by demographic characteristics from the Apple Women’s Health Study
Authors: Huichu Li, Elizabeth A. Gibson, Anne Marie Z. Jukic, Donna D. Baird, Allen J. Wilcox, Christine L. Curry, Tyler Fischer-Colbrie, Jukka-Pekka Onnela, Michelle A. Williams, Russ Hauser, Brent A. Coull, Shruthi Mahalingaiah
Journal: npj Digital Medicine (2023)

Menstrual characteristics are important signs of women's health. Here we examine the variation of menstrual cycle length by age, ethnicity, and body weight using 165,668 cycles from 12,608 participants in the US using mobile menstrual tracking apps. After adjusting for all covariates, mean menstrual cycle length is shorter with older age across all age groups until age 50 and then became longer for those age 50 and older. Menstrual cycles are on average 1.6 (95%CI: 1.2, 2.0) days longer for Asian and 0.7 (95%CI: 0.4, 1.0) days longer for Hispanic participants compared to white non-Hispanic participants. Participants with BMI ≥ 40 kg/m2 have 1.5 (95%CI: 1.2, 1.8) days longer cycles compared to those with BMI between 18.5 and 25 kg/m2. Cycle variability is the lowest among participants aged 35-39 but are considerably higher by 46% (95%CI: 43%, 48%) and 45% (95%CI: 41%, 49%) among those aged under 20 and between 45-49. Cycle variability increase by 200% (95%CI: 191%, 210%) among those aged above 50 compared to those in the 35-39 age group. Compared to white participants, those who are Asian and Hispanic have larger cycle variability. Participants with obesity also have higher cycle variability. Here we confirm previous observations of changes in menstrual cycle pattern with age across reproductive life span and report new evidence on the differences of menstrual variation by ethnicity and obesity status. Future studies should explore the underlying determinants of the variation in menstrual characteristics.
Stakeholder Perspectives on Minimum Clinically Important Difference and Noninferiority Margin for Hospital-Free Days to Assess Interventions
Authors: Catherine L. Auriemma, Maayra I. Butt, Jasmine A. Silvestri, Scott D. Halpern, Katherine R. Courtright
Journal: JAMA Internal Medicine (2023)

This survey study examined perceptions of patients, caregivers and health care professionals on the number of hospital-free days required for detection of a minimum clinically important difference or noninferiority margin of new interventions.
BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Sun Min Lim, Toshio Fujino, Chulwon Kim, Gwanghee Lee, Yong-Hee Lee, Dong-Wan Kim, Jin Seok Ahn, Tetsuya Mitsudomi, Taiguang Jin, Sang-Yoon Lee
Journal: Clinical Cancer Research (2023)

Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.
Spatial Multiplexed Protein Profiling of Cardiac Ischemia-Reperfusion Injury
Authors: Luyan Yao, Funan He, Quanyi Zhao, Dandan Li, Shufang Fu, Mingzhi Zhang, Xingzhong Zhang, Bingying Zhou, Li Wang
Journal: Circulation Research (2023)

Reperfusion therapy is critical to myocardial salvage in the event of a myocardial infarction but is complicated by ischemia-reperfusion injury (IRI). Limited understanding of the spatial organization of cardiac cells, which governs cellular interaction and function, has hindered the search for targeted interventions minimizing the deleterious effects of IRI.We used imaging mass cytometry to characterize the spatial distribution and dynamics of cell phenotypes and communities in the mouse left ventricle following IRI. Heart sections were collected from 12 cardiac segments (basal, mid-cavity, apical, and apex of the anterior, lateral, and inferior wall) and 8 time points (before ischemia [I-0H], and postreperfusion [R-0H, R-2H, R-6H, R-12H, R-1D, R-3D, R-7D]), and stained with 29 metal-isotope-tagged antibodies. Cell community analysis was performed on reconstructed images, and the most disease-relevant cell type and target protein were selected for intervention of IRI.We obtained a total of 251 multiplexed images, and identified 197 063 single cells, which were grouped into 23 distinct cell communities based on the structure of cellular neighborhoods. The cellular architecture was heterogeneous throughout the ventricular wall and exhibited swift changes following IRI. Analysis of proteins with posttranslational modifications in single cells unveiled 13 posttranslational modification intensity clusters and highlighted increased H3K9me3 (tri-methylated lysine 9 of histone H3) as a key regulatory response in endothelial cells during the middle stage of IRI. Erasing H3K9 methylation, by silencing its methyltransferase Suv39h1 or overexpressing its demethylase Kdm4d in isolated endothelial cells, attenuated cardiac dysfunction and pathological remodeling following IRI. in vitro, H3K9me3 binding significantly increased at endothelial cell function-related genes upon hypoxia, suppressing tube formation, which was rescued by inhibiting H3K9me3.We mapped the spatiotemporal heterogeneity of cellular phenotypes in the adult heart upon IRI, and uncovered H3K9me3 in endothelial cells as a potential therapeutic target for alleviating pathological remodeling of the heart following myocardial IRI.
A Pregnant Patient With Narrow QRS Tachycardia
Authors: Kapil Rajendran, Vinayakumar Desabandhu, Pranay Ghanshyam Jambhulkar
Journal: JAMA Internal Medicine (2023)

This case report describes a primigravid patient in their 20s during the eighth month of gestation who presented with history of regular nonexertional episodic palpitations that lasted for a few minutes and subsided spontaneously over the past several days.
Gastric Amphicrine Carcinoma Showing Neuroendocrine and Pancreatic Acinar Cell Differentiation. Lesson from a Challenging Case Opening New Perspectives in the Diagnostic Work-Up of Gastric Neuroendocrine Neoplasms
Authors: Amedeo Sciarra, Silvia Uccella, Philippe Hiroz, Ian Fournier, Vincent Soubeyran, Giovanna Finzi, Stefano La Rosa
Journal: Endocrine Pathology (2023)
Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association
Authors: Carmine Zoccali, Francesca Mallamaci, Marcin Adamczak, Rodrigo Bueno de Oliveira, Ziad A Massy, Pantelis Sarafidis, Rajiv Agarwal, Patrick B Mark, Peter Kotanko, Charles J Ferro, Christoph Wanner, Michel Burnier, Raymond Vanholder, Andrzej Wiecek
Journal: Cardiovascular Research (2023)

Abstract Chronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Cardiovascular complications are the most common causes of death in patients with kidney failure (stage G5) who are maintained on regular dialysis treatment. Because of the high death rate attributable to cardiovascular (CV) disease, most patients with progressive CKD die before reaching kidney failure. Classical risk factors implicated in CV disease are involved in the early stages of CKD. In intermediate and late stages, non-traditional risk factors, including iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders, accumulation of a class of endogenous compounds called ‘uremic toxins’, and a variety of hormonal disorders are the main factors that accelerate the progression of CV disease in these patients. Arterial disease in CKD patients is characterized by an almost unique propensity to calcification and vascular stiffness. Left ventricular hypertrophy, a major risk factor for heart failure, occurs early in CKD and reaches a prevalence of 70–80% in patients with kidney failure. Recent clinical trials have shown the potential benefits of hypoxia-inducible factor prolyl hydroxylase inhibitors, especially as an oral agent in CKD patients. Likewise, the value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown. Sodium/glucose cotransporter-2 inhibitors are now fully emerged as a class of drugs that substantially reduces the risk for CV complications in patients who are already being treated with adequate doses of inhibitors of the renin-angiotensin system. Concerted efforts are being made by major scientific societies to advance basic and clinical research on CV disease in patients with CKD, a research area that remains insufficiently explored.
Aiming to Improve Racial and Ethnic Representation in COVID-19 Trials
Authors: Frederick Green, Zeynep Ersoy Guller, Suhail Aslam
Journal: JAMA Internal Medicine (2023)

Hong Xiao, PhD; Riha Vaidya, PhD; Fang Liu, MD, MMed; Ximing Chang, BS; Xiaoqian Xia, BS; Joseph M. Unger, PhD, MS
Estimated Costs of Intervening in Health-Related Social Needs Detected in Primary Care
Authors: Sanjay Basu, Seth A. Berkowitz, Caitlin Davis, Connor Drake, Robert L. Phillips, Bruce E. Landon
Journal: JAMA Internal Medicine (2023)

Health-related social needs are increasingly being screened for in primary care practices, but it remains unclear how much additional financing is required to address those needs to improve health outcomes.
Multidimensional Sleep Health Prior to SARS-CoV-2 Infection and Risk of Post–COVID-19 Condition
Authors: Siwen Wang, Tianyi Huang, Marc G. Weisskopf, Jae H. Kang, Jorge E. Chavarro, Andrea L. Roberts
Journal: JAMA Network Open (2023)

Importance The association of multiple healthy sleep dimensions with post–COVID-19 condition (PCC), also known as long COVID, has not been investigated. Objective To examine whether multidimensional sleep health before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, was associated with the risk of PCC. Design, Setting, and Participants This prospective cohort study (2015-2021) included Nurses’ Health Study II participants who reported testing positive (n = 2303) for SARS-CoV-2 infection in a substudy series of COVID-19–related surveys (n = 32 249) between April 2020 and November 2021. After exclusion for incomplete information about sleep health and nonresponse to a question about PCC, 1979 women were included in the analysis. Exposures Sleep health was measured both before (June 1, 2015, to May 31, 2017) and early (April 1 to August 31, 2020) in the COVID-19 pandemic. Prepandemic sleep score was defined according to 5 dimensions: morning chronotype (assessed in 2015), 7 to 8 hours of sleep per day, low insomnia symptoms, no snoring, and no frequent daytime dysfunction (all assessed in 2017). On the first COVID-19 substudy survey (returned between April and August 2020), average daily sleep duration and sleep quality for the past 7 days were queried. Main Outcomes and Measures SARS-CoV-2 infection and PCC (≥4 weeks of symptoms) were self-reported during 1 year of follow-up. Comparisons were examined between June 8, 2022, and January 9, 2023, using Poisson regression models. Results Of the 1979 participants reporting SARS-CoV-2 infection (mean [SD] age, 64.7 [4.6] years; 1979 [100%] female; and 1924 [97.2%] White vs 55 [2.8%] other races and ethnicities), 845 (42.7%) were frontline health care workers, and 870 (44.0%) developed PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of developing PCC (multivariable-adjusted relative risk, 0.70; 95% CI, 0.52-0.94; P for trend &amp;amp;lt;.001). Associations did not differ by health care worker status. No or little daytime dysfunction prepandemic and good sleep quality during the pandemic were independently associated with a lower risk of PCC (relative risk, 0.83 [95% CI, 0.71-0.98] and 0.82 [95% CI, 0.69-0.99], respectively). Results were similar when PCC was defined as having 8 or more weeks of symptoms or as having ongoing symptoms at the time of PCC assessment. Conclusions and Relevance The findings indicate that healthy sleep measured prior to SARS-CoV-2 infection, both before and during the COVID-19 pandemic, may be protective against PCC. Future research should investigate whether interventions on sleep health may prevent PCC or improve PCC symptoms.
Use of Metabolic and Bariatric Surgery Among US Youth
Authors: Sarah E. Messiah, Luyu Xie, Nestor de la Cruz-Muñoz, Steven E. Lipshultz
Journal: JAMA Pediatrics (2023)

This cohort study compares trends in use of metabolic and bariatric surgery among US youth and adults before and after publication of a 2019 American Academy of Pediatrics policy statement on access to such surgery.
A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development
Authors: Michael J. Dickinson, Pere Barba, Ulrich Jäger, Nirav N. Shah, Didier Blaise, Javier Briones, Leyla Shune, Nicolas Boissel, Attilio Bondanza, Luisa Mariconti, Anne-Laure Marchal, David S. Quinn, Jennifer Yang, Andrew Price, Akash Sohoni, Louise M. Treanor, Elena J. Orlando, Jennifer Mataraza, Jaclyn Davis, Darlene Lu, Xu Zhu, Boris Engels, Laure Moutouh-de Parseval, Jennifer L. Brogdon, Michele Moschetta, Ian W. Flinn
Journal: Cancer Discovery (2023)

Abstract CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in &amp;lt;2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. Significance: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in &amp;lt;2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949
Volunteering, Health, and Well-being of Children and Adolescents in the United States
Authors: Kevin Lanza, Ethan T. Hunt, Dale S. Mantey, Onyinye Omega-Njemnobi, Benjamin Cristol, Steven H. Kelder
Journal: JAMA Network Open (2023)

This cross-sectional study examines whether there is an association between volunteering and well-being among children and adolescents across the United States.
Primary, Metastatic Tumors Vary Genomically by Cancer Type
Journal: Cancer Discovery (2023)

Turning to a large whole-genome-sequenced tumor cohort, researchers analyzed the genomic differences between primary and metastatic cancers. They found that genomic differences between them were modest except in advanced breast, prostate, thyroid, and kidney renal clear-cell carcinomas and pancreatic neuroendocrine tumors. The researchers showed that one in four patients carries the risk of a genetic immune escape event, primarily from loss of heterozygosity of HLA-I.
An Old Dog Has a New Trick: Somatic Exonic Deletions in<i>RUNX1</i>Are Frequent in AML
Authors: Joyeeta Chakraborty, Kristy R. Stengel
Journal: Clinical Cancer Research (2023)

Summary Somatic loss-of-function RUNX1 mutations in acute myeloid leukemia (AML) include missense, nonsense, and frameshift mutations, whereas germline RUNX1 variants in RUNX1-FPDMM also include large exonic deletions. Alternative variant detection approaches revealed that large exonic deletions in RUNX1 are also common in sporadic AML, which has implications for patient stratification and therapeutic decision-making. See related article by Eriksson et al., p. 2826
Identifying and Mitigating Disparities in Central Line–Associated Bloodstream Infections in Minoritized Racial, Ethnic, and Language Groups
Authors: Caitlin L. McGrath, Brendan Bettinger, Megan Stimpson, Shaquita L. Bell, Tumaini R. Coker, Matthew P. Kronman, Danielle M. Zerr
Journal: JAMA Pediatrics (2023)

Although inequitable care due to racism and bias is well documented in health care, the impact on health care-associated infections is less understood.